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EP0596126A1 - Neue chinolondirivate oder ihre salze und sie enthaltende antibakterielle mittel - Google Patents

Neue chinolondirivate oder ihre salze und sie enthaltende antibakterielle mittel Download PDF

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Publication number
EP0596126A1
EP0596126A1 EP93900445A EP93900445A EP0596126A1 EP 0596126 A1 EP0596126 A1 EP 0596126A1 EP 93900445 A EP93900445 A EP 93900445A EP 93900445 A EP93900445 A EP 93900445A EP 0596126 A1 EP0596126 A1 EP 0596126A1
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group
compound
stirred
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ethyl
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French (fr)
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EP0596126A4 (en
Inventor
Yasuhiro Wakunaga Seiyaku K.K. Kuramoto
Shuichiro Wakunaga Seiyaku Kabushiki Kaisha Noda
Shinobu Wakunaga Seiyaku Kabushikikaisha Maruyama
Shunso Wakunaga Seiyaku Kabushiki Kaisha Hatono
Haruyo Wakunaga Seiyaku Kabushikikaisha Mochizuki
Akira Wakunaga Seiyaku Kabushiki Kaisha Yazaki
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Wakunaga Pharmaceutical Co Ltd
Fujisawa Pharmaceutical Co Ltd
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Wakunaga Pharmaceutical Co Ltd
Fujisawa Pharmaceutical Co Ltd
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Publication of EP0596126A1 publication Critical patent/EP0596126A1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel quinolone derivatives and salts thereof having excellent antibacterial activity and oral-route absorption, and antibacterial agents containing the compounds.
  • the present inventors have conducted careful studies with a view toward obtaining clinically excellent synthetic antibacterial agents, and have found that the compounds represented by formula (1) described hereinafter provide excellent oral absorption, exhibit excellent antibacterial activities against gram negative and gram positive bacteria and thus are very useful as synthetic antibacterial agents, leading to the completion of the invention.
  • the present invention is to provide quinolone derivatives represented by the below-described formula (1), salts thereof and antibacterial agents containing the derivatives or salts: wherein R 1 represents a hydrogen atom, halogen atom or a carboxyl protective group, R 2 represents a hydrogen atom, halogen atom or a lower alkyl group, X represents a hydrogen atom or a halogen atom, Y represents a halogen atom, a cyclic amino group which may have a substituent, a cyclo- lower alkenyl group which may have a substituent, or a group R 3- (CH 2 ) m -A- (wherein R 3 represents a hydrogen atom or an amino group which may have a substituent, A represents an oxygen atom or a sulfur atom and m represents a number of 0 to 3), Z represents a nitrogen atom or a group C-R 4 (wherein R 4 represents a hydrogen atom or a halogen atom), W represents a five
  • the present compounds (1) exhibit excellent antibacterial activities and are highly safe, they are useful as pharmaceuticals for the human and animals, medicines for fishes, pesticides, preservatives for foods, and the like.
  • the term "lower” used in the expressions of the substituents of the quinolone derivatives or their salts (1) means that the group referred to has 1-7, preferably 1-5 carbon atoms when the substituents are linear or branched, and has 3-7 carbon atoms when the substituents are cyclic.
  • the carboxy protective group represented by R 1 is the ester residue of a carboxylic acid ester, and encompasses any groups which are relatively easily cleaved and produce corresponding free carboxyl groups.
  • the carboxy protective group include those removable upon treatment under mild conditions such as hydrolysis or catalytic reduction, such as lower alkyl groups (e.g., methyl, ethyl, n-propyl, t-butyl, etc.), lower alkenyl groups (e.g., allyl, etc.), aralkyl groups (e.g., benzyl, etc.) or aryl groups (e.g., phenyl, etc.); and those readily removable in a living body, such as lower alkanoyloxy-lower alkyl groups (e.g., acetoxymethyl, pivaloyloxymethyl, etc.), lower alkoxycarbonyloxy-lower alkyl groups (e.g., methoxycarbonyloxymethyl, 1-ethoxy
  • lactonyl groups e.g., phthalidyl, etc.
  • di(lower alkyl)amino-lower alkyl groups e.g., 1-dimethylaminoethyl, etc.
  • (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group and the like.
  • Examples of lower alkyl groups represented by R 2 include methyl group, ethyl group, n-propyl group and t-butyl group.
  • halogen atoms represented by X and R 2 include a fluorine atom, chlorine atom, bromine atom, with a fluorine atom being preferred.
  • Halogen atoms represented by Y are the same as those represented by X, among which a fluorine atom and a chlorine atom are preferred.
  • Cyclic amino groups represented by Y, which may have a substituent are saturated or unsaturated, and they may contain further one or more hetero-atoms such as nitrogen, oxygen, sulfur, etc., or a carbonyl carbon in the ring thereof. They may be mono, di, or tri-cyclic.
  • cyclic amino groups include: saturated or unsaturated monocyclic 3 to 7 membered cyclic amino groups having one nitrogen atom, such as azirydin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, dihydropyridin-1-yl, piperidino, dihydroazepin-1-yl, perhydroazepin-1-yl; saturated or unsaturated monocyclic 3 to 7 membered cyclic amino groups having two nitrogen atoms, such as imidazol-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, 1, 4-dihydropyridin-1-yl, 1,2-dihydropyrimidin-1-yl, perhydropyrazin-1-yl and homopiperazin-1-yl; saturated or unsaturated monocyclic 3 to 7 membere
  • E is an oxygen atom, a sulfur atom, -NR 7 or -CONR 7 (R 7 is a hydrogen atom, a hydroxyl group, a lower alkyl group, a cyclo- lower alkyl group, an aralkyl group, an alkenyl group, and acyl group or a hydroxy- lower alkyl group),
  • G is CH or N
  • e is a number of 3-5
  • f is a number of 1-3
  • g is a number of 0-2
  • h is 3 or 4
  • i is 1 or 2.
  • Cyclic atoms of these cyclic amino groups may be substituted with suitable substituents.
  • substituents include lower alkyl groups, lower alkenyl groups, lower aralkyl groups, aryl groups, hydroxyl groups, hydroxy- lower alkyl groups, substituted or unsubstituted amino groups, substituted or unsubstituted amino- lower alkyl groups, cyclic amino groups as mentioned above, alkoxy groups, alkoxy- lower alkyl groups, halogen atoms, halo- lower alkyl groups, acyloxy groups, acyloxy- lower alkyl groups, acyl groups, carboxyl groups, carboxy- lower alkyl groups, alkoxycarbonyl- lower alkyl groups, mercapto groups, lower alkylthio groups, cyano groups and nitro groups.
  • Examples of the lower alkyl groups include methyl group and ethyl group, n-propyl group and the like.
  • Examples of the lower alkenyl groups include vinyl group and allyl group and the like.
  • Examples of the lower aralkyl groups include benzyl group and 1-phenylethyl group and the like.
  • Examples of the aryl groups include phenyl group and the like.
  • Examples of the hydroxy- lower alkyl groups include hydroxymethyl group, hydroxyethyl group, hydroxypropyl group and the like.
  • Examples of the amino- lower alkyl groups include aminomethyl group, 1-aminoethyl group, 2-aminoethyl group, 1-amino-1-methylethyl group and the like.
  • alkoxy groups include methoxy group, ethyoxy group, n-propoxy group and the like.
  • alkoxy- lower alkyl groups include methoxymethyl group, ethoxymethyl group and the like.
  • halogen atoms include fluorine atom, chlorine atom, bromine atom and the like.
  • halo- lower alkyl groups include fluoromethyl group, trifluoromethyl group and the like.
  • acyloxy groups include acetoxy group, benzoyloxy group and the like.
  • acyloxy- lower alkyl groups include acetoxymethyl group benzoyloxymethyl group and the like.
  • acyl groups include lower alkanoyl group such as formyl, acetyl and the like, lower alkoxycarbonyl group such as methoxycarbonyl and ethoxycarbonyl, and aromatic acyl group such as benzoyl, phenoxycarbonyl, and the like.
  • carboxy- lower alkyl groups include carboxymethyl group, carboxyethyl group and the like.
  • alkoxycarbonyl- lower alkyl groups include methoxycarbonylmethyl group, t-butoxycarbonylmethyl group and the like.
  • lower alkylthio groups include methylthio group, ethylthio group and the like.
  • lower alkyl groups e.g., methyl group, ethyl group, etc.
  • lower cycloalkyl groups e.g., cyclopropyl group, cyclobutyl group, cyclopentyl group, etc.
  • lower alkenyl groups e.g., vinyl group, ally group, etc.
  • lower aralkyl groups e.g., benzyl group, 1-phenylethyl group, etc.
  • aryl groups e.g., phenyl group, etc.
  • acyl groups e.g., lower alkanoyl groups such as formyl and acetyl, lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl, etc.
  • amino acid residues or peptide residues e.g., glycyl-, leucyl-, valyl
  • substituted amino group and the substituted amino- lower alkyl group include methylamino group, ethylamino group, dimethylamino group, methylaminomethyl group, ethylaminomethyl group, dimethylaminomethyl group, glycyl-amino group, leucyl-amino group, valyl-amino group, alanyl-amino group, alanyl-alanyl-amino group and the like.
  • R 7 there are given methyl group, ethyl group or the like for the lower alkyl group; cyclopropyl group, cyclobutyl group or the like for the cyclo- lower alkyl group; benzyl group, 1-phenylethyl group or the like for the aralkyl group; vinyl group, allyl group or the like for the alkenyl group; formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group or the like for the acyl group; and hydroxymethyl group, hydroxyethyl group or the like for the hydroxy- lower alkyl group.
  • J 1 , J 2 and J 3 may be the same or different and are one of a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower aralkyl group, an aryl group, a hydroxyl group, a hydroxy- lower alkyl group, a amino group which may have a substituent, a amino- lower alkyl group which may have a substituent, a pyrrolidinyl group, a piperidino group, an azetidinyl group, an alkoxy group, an alkoxy- lower alkyl group, a halogen atom, a halo- lower alkyl group, an acyloxy group, an acyloxy- lower lower
  • heterocyclic ring groups represented by formula (a') include azetidinyl group, pyrrolidinyl group and piperidino group.
  • heterocyclic ring groups represented by formula (b') include piperazinyl group, morpholino group, thiomorpholino group, homopiperazinyl group, thiazolidinyl group, oxazolidinyl group and 3-oxo-1-piperazinyl group.
  • 3-hydroxyazetidinyl group 3-aminoazetidinyl group, 3-(N-t-butoxycarbonylamino)azetidinyl group, 3- acetylamino-azetidinyl group, 3-methylaminoazetidinyl group, 3-dimethyl-aminoazetidinyl group, 3-methylazetidinyl group, 3-amino-2-methylazetidinyl group; pyrrolidinyl group, 3-hydroxy- pyrrolidinyl group, 3,4-dihydroxypyrrolidinyl group, 3-methoxypyrrolidinyl group, 3-methylpyrrolidinyl group, 3-hydroxy-4-methyl-pyrrolidinyl group, 3-aminopyrrolidinyl group, 3-methylaminopyrrolidinyl group, 3-dimethylamino pyrrolidinyl group, 3-ethylaminopyrrolidinyl group, 3-diethyla
  • Examples of the cyclo- lower alkenyl group represented by Y include unsaturated 5 to 7 membered aliphatic carbocyclic groups, such as cyclopentenyl group, cyclohexenyl group and cyclohexedienyl group.
  • Examples of the cyclo- lower alkenyl groups represented by Y which may have a substituent include oxo-cyclohexenyl group, oxo-cyclopentenyl group, amino-cyclohexenyl group and amino-cyclopentenyl group, among which 3-oxo-cyclohexenyl group, 3-oxo-cyclopentenyl group, 3-amino-cyclohexenyl group and 3-amino-cyclopentenyl group are preferred.
  • Z is the group represented by the formula C-R 4
  • the atoms similar to X may be mentioned as the halogen atoms represented by R 4 , among which fluorine atom and chlorine atom are preferred.
  • Example of the five-membered heterocyclic group represented by W which has 3 or more hetero atoms, among which at least 2 hetero-atoms are nitrogen atoms include saturated or unsaturated five-membered heterocyclic group which has two nitrogen atoms and a hetero-atom selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclic group represented by W may be substituted with a suitable substituent such as amino group, above-mentioned substituted amino group, oxo group or the like.
  • substituents are as follows:
  • Examples of the two kinds of substituents R 5 and R 6 in W individually include a hydrogen atom, a lower alkyl group similar to R 2 , and halo lower alkyl groups such as fluoromethyl, trifluoromethyl and fluoroethyl.
  • Preferable examples of the group represented by W include: 1,2,3-thiadiazole-4-yl, 5-methyl-1,2,3-thiadiazole-4-yl, 1,3,4-thiadiazole-2-yl, 5-methyl-1,3,4-thiadiazole-2-yl, 5-trifluoromethyl-1,3,4-thiadiazole-2-yl, 1,2,3-thiadiazole-5-yl, 4-methyl-1,2,3-thiadiazole-5-yl, 1,2,4-thiadiazole-3-yl, 5-methyl-1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl, 3-methyl-1,2,4-thiadiazole-5-yl, 1,2,5-thiadiazole-3-yl, 4-methyl-1,2,5-thiadiazole-3-yl, 4-fluoromethyl-1,2,5-thiadiazole-3-yl, 1,2,3-triazole-4-yl, 1-methyl-1,2,3-triazole-5-yl, 1,2,
  • the quinolone derivatives or salts thereof of formula (1) can be converted into both of acid addition salts and base addition salts, and the salts include those forming chelate salts with boron compounds.
  • acid addition salts include: (a) salts with mineral acids such as hydrochloric acid and sulfuric acid; (b) salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid; and (c) salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • examples of base addition salts include: (a') salts with alkali metals such as sodium and potassium; (b') salts with alkaline earth metals such as calcium and magnesium; (c') ammonium salts; and (d') salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzylamine, N-benzyl-beta-phenethylamine, 1-ephenamine and N,N'-dibenzylethylenediamine.
  • examples of boron compounds include boron halides such as boron fluoride, and lower acyloxy borons such as acetoxy boron,
  • the quinolone derivatives or salts thereof of formula (1) may be not only in unsolvated forms but also in hydrated or solvated forms.
  • the present invention therefore embraces the compounds (1) in any crystalline forms and their hydrated and solvated products.
  • the quinolone derivatives or salts thereof of formula (1) include those containing an asymmetric carbon atom which can exist as optically active substances. These optically active substances are also embraced in the compounds of the present invention.
  • the compounds of formula (1) further include those containing two or more asymmetric carbon atoms which can exist as different stereoisomers (cis-form and trans-form). These stereoisomers are also included in the compounds of the present invention.
  • Each of the quinolone derivatives or salts thereof of formula (1) can be prepared by a process suited for the types of its substituent groups. Preferred preparation processes are as follows.
  • R 1 is a hydrogen atom or a lower alkyl group and Y is a halogen atom
  • R 1a represents a lower alkyl group
  • R 8 represents a lower alkoxy group or a group wherein R11 and R 12 individually represent a lower alkyl group
  • R 9 and R 10 individually represent a lower alkyl group
  • X, Z, W, R 2 and n have the same meaning as defined above.
  • the compound (C) can be obtained by reacting the compound (A) with an orthoformic acid ester (B) such as ethyl orthoformate or methyl orthoformate in acetic anhydride, and then reacting the resulting product with the compound H 2 N-(CH 2 ) n -W.
  • the reaction between the compound (A) and the orthoformic acid ester is conducted generally at 0-160 ° C, preferably at 50-150 °C.
  • the reaction time is generally from 10 minutes to 48 hours, preferably from 1 hour to 10 hours.
  • the orthoformic acid ester (B) can be used in at least an equimolar amount, preferably in a molar amount about 1 to 10 times relative to the compound (A).
  • the subsequent reaction with the compound H 2 N-(CH 2 ) n -W is conducted in a suitable solvent.
  • Any solvent can be used here, as long as it does not affect the reaction.
  • solvents include: aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; dipolar aprotic solvents such as dimethylformamide and dimethylsulfoxide; and alcohols such as methanol, ethanol and propanol.
  • This reaction is conducted generally at 0-150 ° C, preferably at 0-100 ° C.
  • the reaction time generally ranges from 10 minutes to 48 hours.
  • the compound H 2 N-(CH 2 ) n -W can be used in at least an equimolar amount, preferably in a molar amount 1-2 times relative to the compound (A).
  • the compound (C) may be obtained by a reaction of the compound (A) with an acetal such as N,N-dimethylformamide dimethyl acetal or N,N-dimethylformamide diethyl acetal, followed by a reaction with the compound H 2 N-(CH 2 ) n -W.
  • Any solvent may be used for the reaction with the acetal, as long as it is inert to the reaction.
  • the above-mentioned solvents can be used as such inert solvent.
  • This reaction is conducted generally at 0-150 °C, preferably at room temperature to 100 °C.
  • the reaction time is generally from 10 minutes to 48 hours, preferably from 1 to 10 hours.
  • the compound (C) thus obtained is subjected to cyclization reaction to obtain compound (D).
  • This reaction is conducted in a suitable solvent in the presence of a basic compound.
  • Any solvent can be used for this reaction, as long as it does not affect the reaction.
  • solvents include: aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane and monoglyme; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; alcohols such as methanol, ethanol, propanol and butanol; dipolar aprotic solvents such as dimethylformamide and dimethylsulfoxide.
  • basic compounds include: alkali metals such as metallic sodium and metallic potassium; metal hydrides such as sodium hydride and calcium hydride; inorganic bases such as sodium hydroxide, potassium hydroxide and sodium carbonate; alkoxides such as sodium methoxide, sodium ethoxide and potassium-t-butoxide; metal fluorides such as potassium fluoride and sodium fluoride; and organic bases such as triethylamine and 1,8-diazabicyclo [5.4.0]-undecene (DBU).
  • alkali metals such as metallic sodium and metallic potassium
  • metal hydrides such as sodium hydride and calcium hydride
  • inorganic bases such as sodium hydroxide, potassium hydroxide and sodium carbonate
  • alkoxides such as sodium methoxide, sodium ethoxide and potassium-t-butoxide
  • metal fluorides such as potassium fluoride and sodium fluoride
  • organic bases such as triethylamine and 1,8-diazabicyclo [5.
  • the compound (D) thus obtained is further subjected to hydrolysis to obtain compound (E).
  • This reaction can be conducted under reaction conditions which are employed in usual hydrolysis reactions.
  • the hydrolysis reaction is carried out in the presence of a basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; a mineral acid such as hydrochloric acid, sulfuric acid or hydrobromic acid; or an organic acid such as p-toluenesulfonic acid, and in a solvent, e.g.
  • This reaction is conducted generally at room temperature to 180°C, preferably from room temperature to 140°C.
  • the reaction time generally ranges from 1 hour to 24 hours.
  • R 1 is a hydrogen atom or a lower alkyl group
  • Y is a cyclic amino group which may have a substituent, a cyclo lower alkenyl group which may have a substituent, or a group R 3- (CH 2 ) m -A-, wherein R 3 , A and m have the same meaning as defined above
  • X1 represents a halogen atom or a lower alkyl group
  • Y 2 is a cyclic amino group which may have a substituent, a cyclo lower alkenyl group which may have a substituent or a group R 3- (CH 2 ) m -A-, wherein R 3 , A and m have the same meaning as defined above, and R 2 , X, y1 , W and n have the same meaning as defined above.
  • This reaction is carried out in a suitable solvent at room temperature to 160°C, if desired, in the presence of an acid-neutralizing agent such as sodium carbonate, calcium carbonate, sodium hydrogencarbonate, triethylamine or 1,8-diazabicyclo [5.4.0]-undecene (DBU).
  • an acid-neutralizing agent such as sodium carbonate, calcium carbonate, sodium hydrogencarbonate, triethylamine or 1,8-diazabicyclo [5.4.0]-undecene (DBU).
  • solvents which are usable in this reaction include: aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane and monoglyme; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; dipolar aprotic solvents such as dimethylformamide and dimethylsulfoxide; and other solvents which do not adversely affect the reaction such as acetonitrile and pyridine.
  • the reaction can generally be brought to completion in a few minutes to 48 hours, preferably from 10 minutes to 24 hours.
  • the compound Y 2- H may be used in at least an equimolar amount, preferably in a molar amount 1-5 times relative to the compound (F).
  • the group may be substituted with a hydrogen atom by hydrolysis.
  • the starting compounds used in the processes 1 and 2 contain one or more reactive groups which do not take part in the reactions, such as amino group, imino group, hydroxyl group, mercapto group or carboxyl group, these starting compouds may be used in a form with these groups being protected.
  • the protective groups are removed in a general manner after the completion of the reaction. Any group can be used as the protective group, as long as it can be removed without destroying the structure of the compound of the present invention to be formed by the reaction. Groups usually employed in the chemical field of peptides, aminosacchaides and nucleic acids can be used.
  • the starting compound (A) can be prepared by one of the processes described in the following documents or by a similar process:
  • reaction Scheme (3) wherein R lc represents a carboxy protective group, X 2 represents a halogen atom, and R 2 , X, Y, Z, Wand n have the same meaning as defined above.
  • Compound (I) is obtained by reacting the compound (H) with the halogen compound R 1c- X 2 .
  • the preferred solvents include: aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform; dipolar aprotic solvents such as dimethylformamide and dimethyl sulfoxide; and other inactive solvents such as acetonitrile.
  • the reaction is carried out at room temperature to 100 ° C. It is preferred that this reaction be carried out in the presence of a basic compound such as triethylamine, diisopropylethylamine, dicyclohexylamine, DBU, sodium carbonate, potassium carbonate or sodium hydroxide.
  • those containing a primary or secondary amino group as heterocyclic group indicated by Y can be converted to the compounds which have a formimidoyl group or lower alkylimdoyl group on the amino group by reacting with formimidic acid ester or lower alkanecarboximidic acid ester.
  • the compounds of the present invention thus obtained are isolated and purified by methods known per se in the art. They are obtained in the form of salts, free carboxylic acids or free amines, depending on the conditions for isolation and purification. However, they can be converted mutually from one of these forms into another one, whereby the compounds of the present invention can be prepared in a desired form.
  • compositions can be treated as compositions together with pharmaceutical allowable carriers for parenteral dosage such as injection, per rectum, eye instillation and the like and oral administration in the form of solid and solution.
  • compositions for injection Relating to the form of the composition for injection, pharmaceutical allowable axenic water or nonaqueous solution, suspension or emulsion and the like are give.
  • nonaqueous carrier diluent, solution or vehicle, propylene glycol, polyethylene glycol and vegetable oils such as olive oil and injectable organic esters including, for example, oleic acid ethyl are given.
  • compositions may include supplementary agents such as antiseptics, wetting agents, emulsifiers, dispersants and the like.
  • compositions for example, can be sterilized by filtering with a bacteria holding filter or by mixing with a sterilizer in the form of an axenic solid composition soluble in sterilized water or other several sterilized injectable solutes or media right before the use.
  • the preparation for eye instillation dosage can preferably include dissolution adjuvants, preservatives, isotonic agents, mucilages and the like.
  • the solid preparations for oral dosage can include capsules, tablets, pills, powders and granules.
  • the compound of the present invention is mixed with at least one kind of an inert diluent such as sucrose, lactose or starch.
  • the preparations can further include a supplementary material except the inert diluent, for example, a lubricant such as magnesium stealate or the like.
  • the capsules, tablets and pills can further include a buffer. The tablets and pills can further apply an enteric coat thereon.
  • the solution preparations for oral dosage can include inert diluents usually used by a person skilled in the art, for instance, pharmaceutical allowable emulsifiers including water, solutions, suspensions, syrups and elixirs.
  • inert diluents usually used by a person skilled in the art, for instance, pharmaceutical allowable emulsifiers including water, solutions, suspensions, syrups and elixirs.
  • the compositions can be blended with supplementary agents such as wetting agents, emulsifiers, suspensions, edulcorants, flavors and perfumes.
  • the preparations for per rectum dosage may preferably include excipients such as cocoa butter or suppository wax in addition to the compound of the present invention.
  • the dose of the compound represented by general formula (1) depends on the properties of the compound to be dosed, dosing route, the desired treating period and other factors, and is, in general, approximately 0.1 to 1000 mg/kg a day, and preferably approximately 1 to 100 mg/kg a day. If necessary, this dose for one day can be divided into 2-4 times.
  • Example 28 Compound No.64 (0.18g) obtained in Example 28 was dissolved in acetic acid (1 ml) and 6N-HCI (1ml). The solution was stirred at 100°C for 1 hour. Water (30ml) was added thereto, and the solid matter was collected by filtration, followed by washing with water, ethanol and ether successively. The title compound No. 65 was obtained as a yellow solid (115mg).
  • Example 34 Compound No.73 (1.2g) obtained in Example 34 was dissolved in a mixture of tetrahydrofuran (40ml) and HCI (10ml). The solution was reacted at 100°C for 40 minutes. After evaporation, to the residue was added water, and the solid matter was collected by filtration, followed by washing with water, ethanol, ether and n-hexane, successively. The title compound No. 74 was obtained as a pale brown solid (0.9g).
  • Example 158 Compound No.112 (0.4g) obtained in Example 158 was dissolved in acetic acid (4.5ml) and 6N-HCI (1.5ml). The solution was stirred at 100°C for 2 hours. After cooling, the precipitate was filtrated and washed with water, ethanol and ether. The title compound No. 113 was obtained as a pale yellow solid (0.33g).
  • Example 63 Compound No.118 (0.42g) obtained in Example 63 was dissolved in acetic acid (6ml) and 6N-HCI (2ml). The solution was stirred at 100°C for 2 hours. After cooling, the precipitate was filtrated and washed with water, ethanol and ether. The title compound No. 119 was obtained as a colorless solid (0.325g).
  • Example 67 Compound No.124 (0.38g) obtained in Example 67 was dissolved in acetic acid (4.5ml) and 6N-HCI (1.5ml). The solution was stirred at 100°C for 1.5 hours. After cooling, ethanol (3ml) was added thereto, and the precipitate was filtrated, followed by washing with ethanol and ether. The title compound No. 125 was obtained as a colorless solid (0.34g).
  • Example 76 Compound No.137 (0.05g) obtained in Example 76 was suspended in tetrahydrofuran (20ml), to which an aqueous 1N-NaOH solution (0.13ml) was added. The solution was stirred at room temperature for 3 days. After evaporation of the solvent, chloroform was added. The precipitate was filtrated. The title compound No. 138 was obtained as a pale brown solid (42mg).
  • Example 82 Compound No.144 (0.1g) obtained in Example 82 was dissolved in tetrahydrofuran (10ml) and 1 N-NaOH (0.3ml). The solution was stirred at room temperature overnight. After addition of chloroform, the precipitate was filtrated, followed by washing with chloroform. The title compound No. 145 was obtained as a pale yellow solid (77mg).
  • Compound No. 157 (colorless needles) was prepared in a similar manner to Example 17, proceeding from the corresponding compounds ethyl 2-methyl-3,4,6,-trifluorobenzoylacetate, ethyl orthoformate, acetic anhydride and 3-amino-1,2,5-thiadiazole hydrochloride.
  • Example 111 Compound No.180 (2g) obtained in Example 111 was dissolved in a solution of acetic acid (10ml) and 6N-HCI (10ml). The solution was stirred at 100°C for 1 hour, and the solvent was removed. After addition of water (100ml) to the residue, the precipitate was filtrated and washed with ethanol and ether. The title compound No. 181 was obtained as a pale yellow solid (1.1 g).
  • Example 115 Compound No.185 (15.1g) obtained in Example 115 was dissolved in acetic acid (180ml) and c-HCI (80ml). The solution was stirred for 1 hour with heating under reflux. After cooling, water (200ml) was added thereto. The precipitate was filtrated and washed with water, ethanol and ether. The title compound No. 186 was obtained as pale yellow needles (13.3g).
  • This compound can also be obtained as slightly yellow needles by crystallizing from water. It decomposes at a temperature of 299 °C or higher.
  • the melting point and the 1 H-NMR data of the compound 195 are as follows: Melting point: 170-177 °C
  • This compound is an ethyl ester derivative of compound No.244.
  • MIC microgram/ml
  • a subject compound was orally administered as prepared to be 20 mg/10ml/kg with 0.5% of methylcellulose solution.
  • the sampling was carried out by collecting urine in 0 to 6 hours and 6 to 24 hours.
  • the concentration of the subject compound in the urine was examined by a disk method by using Bacillus subtilis ATCC 6633 as a testing bacillus to obtain an excretion rate in urine for 24 hours.
  • a subject compound was prepared in the same manner as the recovery test in urine and was orally administered to the rats.
  • the bile was collected by using a polyethylene tube inserted into the choledochus over 24 hours.
  • the concentration of the subject compound in the bile sample was examined in the same manner as the recovery in urine to obtain an excretion rate in bile for 24 hours.
  • the compounds represented by formula(1) and salts thereof which are novel compounds, exhibit an extremely excellent antibacterial activity against gram- negative and gram-positive bacteria and possess a high oral absorbability.
  • the compounds represented by formula (1) and salts thereof are extremely valuable as antibacterial agents and very safe. Accordingly, they can be used as not only pharmaceuticals or medicines for the human body and animals but also medicines for fishes, agricultural chemicals and preservatives for foods. Further, the compounds of this invention are expected to have an anti viral action, especially an anti-HIV (human immuno deficiency virus) action, and therefore is considered to have preventive or curative activities against the AIDS.
  • an anti viral action especially an anti-HIV (human immuno deficiency virus) action

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EP19930900445 1991-12-27 1992-12-25 Novel quinolone derivative or salt thereof and antibacterial containing the same. Withdrawn EP0596126A4 (en)

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JP34657791 1991-12-27
JP346577/91 1991-12-27
PCT/JP1992/001712 WO1993013091A1 (fr) 1991-12-27 1992-12-25 Nouveau derive de quinolone ou sel de ce derive et agent antibacterien contenant ce derive

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WO1996006848A1 (de) * 1994-09-01 1996-03-07 Bayer Aktiengesellschaft NEUE THIAZOLO[3,2-a]CHINOLIN- UND -NAPHTHYRIDINDERIVATE
US7012074B2 (en) 2000-10-20 2006-03-14 Astrazeneca Ab 3,8-Diazabicyclo[3.2.1]octanes and their use in the treatment of cardiac arrhythmias
WO2005100349A3 (en) * 2004-04-13 2006-03-16 Icagen Inc Polycyclic pyridines as potassium ion channel modulators
WO2006123792A1 (ja) * 2005-05-19 2006-11-23 Daiichi Sankyo Company, Limited トリ－、テトラ－置換－３－アミノピロリジン誘導体
EP1610795A4 (de) * 2003-04-07 2007-10-24 Cylene Pharmaceuticals Inc Heterocyclische substituierte 1,4-dihydro-4-oxo-1,8-naphthpyridin-analoga
RU2420524C2 (ru) * 2005-05-19 2011-06-10 Дайити Санкио Компани, Лимитед Производные три- или тетра-замещенного-3-аминопирролидина
CN102627630A (zh) * 2012-03-16 2012-08-08 西南大学 喹诺酮类化合物及其制备方法和应用
CN110520422A (zh) * 2017-03-24 2019-11-29 涌永制药株式会社 新型吡啶酮羧酸衍生物或其盐

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WO1996006848A1 (de) * 1994-09-01 1996-03-07 Bayer Aktiengesellschaft NEUE THIAZOLO[3,2-a]CHINOLIN- UND -NAPHTHYRIDINDERIVATE
AU685671B2 (en) * 1994-09-01 1998-01-22 Bayer Aktiengesellschaft New thiazolo{3,2-a}quinoline and thiazolo{3,2-a}naphthyridine derivatives
US5744478A (en) * 1994-09-01 1998-04-28 Bayer Aktiengesellschaft Thiazolo 3,2-a! quinoline and thiazolo 3,2-a! naphthyridine derivatives
US7012074B2 (en) 2000-10-20 2006-03-14 Astrazeneca Ab 3,8-Diazabicyclo[3.2.1]octanes and their use in the treatment of cardiac arrhythmias
EP1610795A4 (de) * 2003-04-07 2007-10-24 Cylene Pharmaceuticals Inc Heterocyclische substituierte 1,4-dihydro-4-oxo-1,8-naphthpyridin-analoga
WO2005100349A3 (en) * 2004-04-13 2006-03-16 Icagen Inc Polycyclic pyridines as potassium ion channel modulators
WO2006123792A1 (ja) * 2005-05-19 2006-11-23 Daiichi Sankyo Company, Limited トリ－、テトラ－置換－３－アミノピロリジン誘導体
US7563805B2 (en) 2005-05-19 2009-07-21 Daiichi Pharmaceutical Co., Ltd. Tri-, tetra-substituted-3-aminopyrrolidine derivative
RU2420524C2 (ru) * 2005-05-19 2011-06-10 Дайити Санкио Компани, Лимитед Производные три- или тетра-замещенного-3-аминопирролидина
US8211910B2 (en) 2005-05-19 2012-07-03 Daiichi Pharmaceutical Co., Ltd. Tri-, tetra-substituted-3-aminopyrrolidine derivative
US8476429B2 (en) 2005-05-19 2013-07-02 Daiichi Sankyo Company, Limited Tri-, tetra-substituted-3-aminopyrrolidine derivative
CN102627630A (zh) * 2012-03-16 2012-08-08 西南大学 喹诺酮类化合物及其制备方法和应用
CN110520422A (zh) * 2017-03-24 2019-11-29 涌永制药株式会社 新型吡啶酮羧酸衍生物或其盐
CN110520422B (zh) * 2017-03-24 2023-09-05 涌永制药株式会社 新型吡啶酮羧酸衍生物或其盐

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US5412098A (en) 1995-05-02

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